补骨脂宁通过激活Nrf2/HO-1并抑制NF-κB信号通路在过氧化氢诱导的HT22细胞和脂多糖诱导的BV2细胞上发挥抗氧化和抗神经炎症作用  

Anti-oxidative and anti-neuroinflammatory effects of corylin in H_(2)O_(2)-induced HT22 cells and LPS-induced BV2 cells by activating Nrf2/HO-1 and inhibiting NF-κB pathways

作　　者：王昭景 许青霞 许京 徐嵬 杨秀伟 Zhaojing Wang;Qingxia Xu;Jing Xu;Wei Xu;Xiuwei Yang(State Key Laboratory of Natural and Biomimetic Drugs,Department of Natural Medicines,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China)

机构地区：[1]北京大学医学部药学院天然药物学系、天然药物及仿生药物国家重点实验室,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2023年第2期85-100,共16页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No.81773865).

摘　　要：氧化损伤和神经炎症与许多神经系统疾病相关。近年来,研究发现中药补骨脂能够改善中枢神经系统损伤。本研究旨在评价两个来自补骨脂的化合物:补骨脂宁和补骨脂定的神经保护作用,并揭示其作用机制。实验结果表明,补骨脂宁和补骨脂定能够抑制过氧化氢(H_(2)O_(2))诱导的小鼠海马神经原代细胞(HT22)活性氧(ROS)的生成,抑制脂多糖(LPS)诱导的小鼠神经小胶质细胞(BV2)一氧化氮(NO)的生成。由于补骨脂宁在低剂量即表现出活性,且在高剂量时未表现出细胞毒,因此进一步研究其潜在的神经保护作用机制。在H_(2)O_(2)诱导的HT22细胞中,补骨脂宁显著增加过氧化氢酶(CAT)、超氧化物歧化酶(SOD)活性,促进谷胱甘肽(GSH)分泌,抑制线粒体膜电位(MMP)降低。同时上调Nrf2和HO-1蛋白在HT22细胞中的表达。在LPS诱导的BV2细胞中,补骨脂宁显著抑制炎症因子IL-1β、IL-6和TNF-α的分泌,并能够特异性抑制NF-κBp65转移入核。分子对接结果显示:补骨脂宁能够进入Keap1和NF-κB蛋白的疏水口袋,结合良好。本研究证实,补骨脂宁能够改善H_(2)O_(2)诱导的氧化损伤和LPS诱导的神经炎症,其作用机制可能与Nrf2/HO-1和NF-κB信号通路有关。Oxidative damage and neuroinflammation are associated with numerous neurological diseases.In recent years,Psoraleae Fructus(dried fruits of Psoralea corylifolia L.),a traditional Chinese medicine,has been found to have medicinal properties in ameliorating central nervous system(CNS)injury.This study aimed to evaluate two neuroprotective compounds of Psoraleae Fructus:corylin and psoralidin,and reveal their underlying mechanisms.The results showed that corylin and psoralidin suppressed reactive oxygen species(ROS)production in H_(2)O_(2)-induced HT22 cells and nitric oxide(NO)production in lipopolysaccharide(LPS)-induced BV2 cells.Further mechanism research of corylin was carried out owing to its better safety and efficacy.In H_(2)O_(2)-induced HT22 cells,corylin significantly increased catalase(CAT),superoxide dismutase(SOD)activity,and glutathione(GSH)expression,while it inhibited mitochondrial membrane potential(MMP)reduction.Meanwhile,the expressions of Nrf2 and HO-1 were up-regulated.In LPS-induced BV2 cells,corylin markedly inhibited IL-1β,IL-6,and TNF-αexpressions and specifically suppressed NF-κB p65 nuclear translocation.Furthermore,the docking analysis showed that corylin penetrated well into the hydrophobic pockets of Keap 1 and NF-κB protein.This study demonstrated that corylin alleviated oxidative damage and neuroinflammation by activating Nrf2/HO-1 and inhibiting NF-κB pathways,suggesting its potential ability to treat neurological diseases.

关 键 词：补骨脂宁 氧化损伤 神经炎症 NRF2 NF-κB 

分 类 号：R285.5[医药卫生—中药学]